NIH Public Access Author Manuscript Res Gerontol Nurs. Author manuscript; available in PMC 2015 March 01.
NIH-PA Author Manuscript
Published in final edited form as: Res Gerontol Nurs. 2014 March ; 7(2): 56–65. doi:10.3928/19404921-20131018-01.
Biobehavioral Measures as Outcomes: A Cautionary Tale Christine R. Kovach, PhD, RN, FAAN [Professor], University of Wisconsin-Milwaukee, Milwaukee, Wisconsin Diana Lynn Woods, PhD, RN, APRN-BC, FGSA [Associate Professor], Azusa Pacific University School of Nursing, Azusa, CA 91702-7000 Elizabeth C. Devine, PhD, RN [Professor Emeritus], University of Wisconsin-Milwaukee, Milwaukee, Wisconsin Brent R. Logan, PhD [Professor], and Medical College of Wisconsin, Milwaukee, Wisconsin
NIH-PA Author Manuscript
Hershel Raff, PhD [Professor of Medicine, Surgery, and Physiology] Medical College of Wisconsin Endocrine Research Laboratory, Aurora St. Luke’s Medical Center, Aurora Research Foundation Milwaukee, Wisconsin Diana Lynn Woods: [email protected]
Abstract This article discusses the use of biobehavioral measures as outcomes for healthcare intervention studies. Effect size (ES) values for salivary cortisol, and observation-based measures of pain and agitation are examined. Effects pre to post treatment were assessed separately for nursing home (NH) residents with and without acute psychotic symptoms. This study revealed large positive effects on both pain and agitation measures in the group with acute psychotic symptoms and small-to-medium positive effects on these same measures in the group without acute psychotic symptoms. In both of these groups the ES values were not consistently positive on the cortisol measures. Prior to determining if a measure can be used to estimate minimum clinically important differences, it is essential to consider if the biomarker will be responsive to therapy in the populations and contexts being studied.
NIH-PA Author Manuscript
Keywords aging; dementia; stress; endocrine system In recent years there has been increased emphasis on including biological measures in health care research and in evaluating patient outcomes. The National Institute for Nursing Research (NINR) has emphasized the need for more biobehavioral research (https:// www.ninr.nih.gov/sites/www.ninr.nih.gov/files/ninr-strategic-plan-2011.pdf) and the Institute of Medicine (IOM) of the National Academies (IOM, 2010) released a report discussing the issues associated with using biological measures as surrogate endpoints for patient outcomes. Biobehavioral research is grounded in the premise that understanding and influencing health outcomes is enhanced through examining the links between biological, psychosocial, and behavioral factors and health status/outcomes (Pellmar, Brandt, & Baird, 2002). This is a worthy goal; however, the success of biobehavioral science in making new Correspondence concerning this article should be addressed to: Christine R. Kovach, College of Nursing, University of Wisconsin Milwaukee, 1921 E Hartford Ave, Milwaukee, WI 53201-0413. [email protected]. The authors declare no conflict of interest.
Kovach et al.
Page 2
NIH-PA Author Manuscript
inroads that influence health outcomes is dependent on understanding and attending to the complexities of a host of specialized conceptual and methodological challenges associated with using biological measures in research.
NIH-PA Author Manuscript
As noted in the IOM report cited above, consistent scientific processes and frameworks are needed in order to ensure the rigorous and transparent use of biological measures. In addition to possibly being invasive and costly, given the state of the science, the selection and interpretation of biological measures must be done with caution. For some biological measures we are lacking strong evidence on the natural history of variability over time and on predictors of variability in the measure. There is a need to build a strong research base on the ability of biological measures to capture meaningful change and to determine minimum clinically important differences (MCID). The purpose of this article is to explore some issues regarding the use of biological measures as outcomes in nursing studies. Data from a study testing the effects of a nurse assessment and treatment protocol used to treat nursing home (NH) residents with dementia are presented (Kovach, Logan, et al., 2006). The purpose of these results is not to look for treatment effects; rather it is to highlight the specific methodological issue of measurement responsiveness to therapy. Effect sizes (ES) for salivary cortisol, observer-rated pain and agitation are presented for two groups of NH residents who were being assessed and treated for new problems over six weeks. For this secondary analysis we compared NH residents who developed new acute psychotic symptoms to NH residents who developed other new problems (e.g. arthrtitic pain, constipation, infection). Because acute psychosis is associated with high stress, these two groups provided an opportunity to examine outcomes following treatment in two different populations.
MCID AND RESPONSIVENESS TO CHANGE The determination of MCID is needed for evaluating the clinical meaningfulness of statistically significant research findings. MCID is defined as an estimation of the smallest difference in a measurable clinical parameter that indicates a meaningful change in a health care outcome (Kiley, Sri Ram, Croxton, & Weinmann, 2005). The development and use of standardized MCIDs will increase the evidence-base for nursing practice, assist in making decisions regarding resource allocation, and allow clearer interpretation of research findings.
NIH-PA Author Manuscript
While MCIDs have value, there are notable challenges to developing metrics for MCIDs (Gilbert, Brown, Cappelleri, Carlsson, & McKenna, 2009; Jordon, Dunn, Lewis & Croft, 2006). Even with fairly well-accepted biological measures, it is possible that as science develops we will learn that a measure may be able to detect change under some conditions, but not under other conditions. Therefore it is important to consider theory, previous research, and the expected change from treatment when deciding if it is reasonable to select a particular biological measure for a specific study. An essential quality of the measure used to develop the MCID, is the ability to accurately detect health change in response to a specific treatment or stimuli. The measure should validly represent the intended construct. While determining this is not trivial, it can be particularly challenging for biological measures which may have well-established measurement validity for the biological phenomenon being measured (e.g., it validly measures the serum level of a hormone) but which may, or may not have, well-established measurement validity for the intended outcome construct of the study (e.g., stress). In addition, the outcome measure used should remain relatively unchanged if the treatment is not administered (i.e., it must have test-retest reliability), there must be room for change on the measure (e.g., it should not have a floor or ceiling effect), and the timing of measurement must be appropriate for the onset and duration of the intervention’s effect.
Res Gerontol Nurs. Author manuscript; available in PMC 2015 March 01.
Kovach et al.
Page 3
NIH-PA Author Manuscript
Once a measure is deemed reasonable, pilot work can estimate the direction and magnitude of changes on the measure following the proposed treatment or stimuli condition. This estimate can be used in ad hoc power analysis and to determine if the estimated amount of change is clinically significant. A statistically significant change in group scores following treatment on a biomarker does not necessarily indicate an important change in health or quality of life. In order for a biomarker to qualify as a MCID, the change in score needs to relate to other measures (Jordon et al., 2006). For example, in people with dementia, these might include family report of improvement or changes in psychotropic drug use. The change in the biomarker should also not have a negative consequence on the overall health status of the individual. For example ezetimibe significantly lowers cholesterol but is related to severe hepatic side effects (Stolk, Becx, Kuypers & Seldenrijk, 2006).
BACKGROUND TO STUDY OF PEOPLE WITH ADVANCED DEMENTIA
NIH-PA Author Manuscript
The Serial Trial Intervention (STI) is a decision support tool to address the problem of under assessment and treatment of newly emerging problems of nursing home residents with advanced dementia that are unable to clearly or consistently verbally report symptoms. The estimates of treatment effect used in this study are based on data from a parent study that compared the effects of two versions of a nursing assessment and treatment protocol (5-step and 9-step Serial Trial Intervention) on stress, pain, and agitation among NH residents with advanced dementia (Kovach et al., 2012). The 5-step version of the STI was tested for the outcomes of pain and agitation and found to be effective when compared to standard care (Kovach, Kelber, Simpson, & Wells, 2006). However, it was also found that thoughtful follow through was often lacking as evidenced by failure to get effective treatments scheduled for regular use and failure to add adjunctive and preventive therapies to the therapeutic regimen (Kovach, Cashin, et al., 2006). The 9step version attempted to address these deficits by adding steps that directed nurses to provide more long-term and more comprehensive treatments and to perform more thorough evaluations (Kovach et al., 2012).
NIH-PA Author Manuscript
The physical condition and functional limitations of people with advanced dementia pose challenges to measurement of variables of interest in nursing research. People with advanced dementia have communication and cognitive deficits that preclude the use of most selfreport measures. Proxy reports from family and professional caregivers on measures such as pain are highly biased. For example, multiple studies have found that family and professional caregivers grossly underestimate pain and depression in people with dementia (Horgas & Dunn, 2001; Cohen-Mansfield & Lipson, 2002). Also, invasive measures or those that involve application of sensors to the body may induce a response that confounds the measurement (Aung et al., 2008). The use of physiological variables to measure indices of stress and depression has been driven, in part, by technological advances that enable the noninvasive measurement of some biological measures. Cortisol can be easily accessed by saliva collection that can be accomplished in everyday contexts with minimal interruption to the natural flow of activities. This is an important consideration for debilitated NH residents. Several studies have demonstrated a strong correlation (r = .805) between time-matched salivary and plasma cortisol (Hellhammer, Wust, & Kudielka, 2009; Kirschbaum & Hellhammer, 1994; Pruessner et al., 1997). Saliva collection has been shown to be well tolerated by NH residents (Woods et al., 2008). The acceptability of saliva collection is important so that cortisol levels are not confounded by an induced stress response from sample collection.
Res Gerontol Nurs. Author manuscript; available in PMC 2015 March 01.
Kovach et al.
Page 4
These samples are also stable for up to 2 weeks at room temperature (Malamud, 1992), thus eliminating the need for immediate freezing.
NIH-PA Author Manuscript
Key conceptual issues in attempting to incorporate cortisol as an outcome measure into intervention studies for intervention studies include justifications for : a) cortisol as a marker of physical and emotional stress; b) the ability of people with dementia to experience stress from a threat or challenge; and c) the relationship of treatment of the threat or challenge to lower stress. While salivary cortisol has been used as a measure in psychophysiological research for the past 20 years (Kirschbaum & Hellhammer, 1989), this measure has begun to be used more recently in nursing and dementia care research (Hanrahan, McCarthy, Kleiber, Lutgendorf, & Tsalikian, 2006; Herrington, Olomu, & Geller, 2004; Williams, Hagerty, & Brooks, 2004; Woods & Dimond, 2002; Woods & Martin, 2007). Salivary cortisol is frequently used as a biomarker of psychological stress (Piazza, Almeida, Dmitrieva, & Klein, 2010) and measurement of cortisol in saliva provides a reliable marker of stress resulting from both physical discomfort and emotional stress (Chrousos, 2011; Weibel, 2003; Young, Abelson, & Lightman, 2004).
NIH-PA Author Manuscript
Stress is defined as a physiological response of the body to situations or stimulus that are perceived as dangerous or threatening. People with dementia have a decreased threshold for tolerating such stressors (Lawton, 1986; Hall & Buckwalter, 1987). Multiple studies have shown an association between stress, emotional arousal and salivary cortisol levels (Blair et al, 2008; El-Sheikh, Erath, Buckhalt Granger, & Mize, 2008; Fortunato, Dribin, Granger, & Buss, 2008). Age can influence cortsiol values. The most consistent finding with advanced age is an increase in the nighttime nadir which flattens the slope (Ice, 2005; Fiocco, Wan, Weekes, Pim, & Lupien, 2006; Raff et al, 1999; Smyth et al, 1997). Treatment of physical and emotional stress is associated with lowering of cortisol level (Carlson, Speca, Patel & Goodey, 2004; Gaab, Blattler, Menzi, Pabst, Stoyer & Ehlert, 2003; Woods & Dimond, 2002).
METHODS Design and Sample
NIH-PA Author Manuscript
Study participants for this secondary analysis were from twelve NHs, all of which had a typical schedule of early awakening (i.e. 5:00 a.m. to 8:00 a.m.) and early bedtime (5:40 p.m. to 8:00 p.m.). The inclusion criteria from the parent study were that the person had a diagnosis of a dementing illness, had no other chronic psychiatric diagnosis, had no known diseases of the hypothalamic-pituitary-adrenal axis, was not taking a corticosteroid, had a pre-study length of stay in the NH of at least 4 weeks, and had no diagnosed acute illness at pretesting. Participants from the two study conditions were combined because the direction and magnitude of effects for the two-week time period examined in the data used for this study were similar across the two versions of the protocol. The study was approved by the Institutional Review Board. Written consent was obtained from the NH resident’s guardian and verbal assent was obtained from each participant asked to participate. While all participants provided assent, five participants clearly refused or expressed displeasure regarding saliva collection. Samples were not collected when a participant refused or expressed any sign of displeasure regarding the data collection. It is worth noting that as is typical for NH residents, many patients were being treated for common conditions that included infection (e.g., of the skin, urinary tract, respiratory tract, or gastrointestinal tract), pain (e.g., musculoskeletal or neuropathic), mobility or body alignment problems, skin breakdown, constipation, leg swelling from venous insufficiency, impacted cerumen, poor dentition, and dysphagia. For the current study two samples were
Res Gerontol Nurs. Author manuscript; available in PMC 2015 March 01.
Kovach et al.
Page 5
identified: participants being treated for new acute problems without acute psychosis (n = 95) and participants who were being treated for new acute psychotic symptoms (n = 16).
NIH-PA Author Manuscript
Thirty-one NH residents from the parent study were excluded from this study: 10 were in the dying process, 9 were hospitalized for acute illness (e.g. stroke, bradycardia, heart failure, unresponsive episode), 6 had saliva containing exogenous hydrocortisone documented by liquid chromatograph/tandem mass spectrometry (Raff & Singh, 2012), and 6 had missing saliva samples due to collection refusal (n =5) or quantity not sufficient (n =1). Measures and Procedures
NIH-PA Author Manuscript
Salivary cortisol was used to measure HPA axis response to stress (Raff, 2000). The Wisconsin Agitation Intensity (WAI) Scale, used to measure agitated behavior, is an observational scale that uses number, duration and intensity of behaviors as parameters for agitation severity. Possible scores are 0 to 100. Interrater reliability using this tool is .95–.98 and the scale demonstrated responsiveness to change following intervention (Kovach et al., 2004). Pain was assessed using the 9-item Discomfort-DAT scale (Hurley, Volicer, Hanrahan, Houde, & Volicer, 1992). Possible scores are 0 to 75. It is an observational tool that assesses overall level of discomfort rather than pain in response to acute stimuli. Internal consistency alpha coefficients have been reported between .86 and .89 (Hurley et al., 1992) and interrater reliability of .9 (Kovach, Noonan et al., 2006). In the latter study, which was a randomized experiment, the tool demonstrated responsiveness to change following intervention. Saliva and observation-based measures of agitation and pain were collected on the same weekday, both before the nurses began using the assessment and treatment protocol and two weeks after treatment was initiated. Three nurse research assistants, not employed by the nursing homes, were trained by the principal investigator to screen for eligibility, to conduct unobtrusive observations of agitation and pain, and to collect the saliva samples. Data collectors were blinded to study conditions.
NIH-PA Author Manuscript
Measures of pain and agitation were collected at least 30 minutes past the time of any potentially discomfort or stress-producing event (e.g., bath, medical exam). Since agitation typically fluctuates over the day, multiple measurements at various time points are recommended to provide a reasonable measure of overall agitation (Kovach et al., 2004). Eight agitation measures were taken per day (2 during breakfast, midmorning, before and after dinner). To capture possible differences in overall level of discomfort in the morning and afternoon, two Discomfort-DAT measures were taken per day. To derive an overall assessment of daily pain and agitation, scores were averaged to yield one pretest and one posttest score on each measure for each study participant. Evidence supports the use of a similar physiological stimulus such as food intake during regular mealtimes to stimulate the HPA axis and control for some intraindividual variation in diurnal rhythm (Gibson et al., 1999; Rosmand, Holm, & Bjorntorp, 2000). It is also recommended that saliva for cortisol assay be obtained close to awakening and bedtime to capture diurnal variation in cortisol levels (Stone et al., 2001). Because residents of many nursing homes retire to bed early in the evening, 45 minutes after dinner was a feasible data collection time that is close to nadir. Four saliva samples were collected (±15 minutes) from under the tongue: 30 minutes after waking (T1-waking), 45 minutes after breakfast (T2-morning), and 45 minutes before (T3afternoon) and after dinner (T4-evening). Following collection, samples were inserted into a cryogenic vial or storage tube, centrifuged, batched by subject, and frozen at −20°C. Saliva samples were analyzed using an FDA-cleared cortisol ELISA (Salimetrics, LLC, State College, PA; Raff, Homar, & Skoner, 2003). Samples from each subject were assayed in one batch. The intraassay imprecision, expressed as a coefficient of variation, (CV) was Res Gerontol Nurs. Author manuscript; available in PMC 2015 March 01.
Kovach et al.
Page 6
NIH-PA Author Manuscript
5.2% at 3.1 (SD, 0.2) nmol/L (n = 10) and 2.6% at 10.4 (0.3) nmol/L (n = 10). Intrassay imprecision is the analytical error for samples analyzed within a single run of the assay. In the current study, samples from each subject were analyzed within one run to minimize interassay imprecision described below. It is typical of immunoassays to have higher CVs at the lowest concentrations of the analyte measured. It is important to note that an intraassay CV of
NIH-PA Author Manuscript
Published in final edited form as: Res Gerontol Nurs. 2014 March ; 7(2): 56–65. doi:10.3928/19404921-20131018-01.
Biobehavioral Measures as Outcomes: A Cautionary Tale Christine R. Kovach, PhD, RN, FAAN [Professor], University of Wisconsin-Milwaukee, Milwaukee, Wisconsin Diana Lynn Woods, PhD, RN, APRN-BC, FGSA [Associate Professor], Azusa Pacific University School of Nursing, Azusa, CA 91702-7000 Elizabeth C. Devine, PhD, RN [Professor Emeritus], University of Wisconsin-Milwaukee, Milwaukee, Wisconsin Brent R. Logan, PhD [Professor], and Medical College of Wisconsin, Milwaukee, Wisconsin
NIH-PA Author Manuscript
Hershel Raff, PhD [Professor of Medicine, Surgery, and Physiology] Medical College of Wisconsin Endocrine Research Laboratory, Aurora St. Luke’s Medical Center, Aurora Research Foundation Milwaukee, Wisconsin Diana Lynn Woods: [email protected]
Abstract This article discusses the use of biobehavioral measures as outcomes for healthcare intervention studies. Effect size (ES) values for salivary cortisol, and observation-based measures of pain and agitation are examined. Effects pre to post treatment were assessed separately for nursing home (NH) residents with and without acute psychotic symptoms. This study revealed large positive effects on both pain and agitation measures in the group with acute psychotic symptoms and small-to-medium positive effects on these same measures in the group without acute psychotic symptoms. In both of these groups the ES values were not consistently positive on the cortisol measures. Prior to determining if a measure can be used to estimate minimum clinically important differences, it is essential to consider if the biomarker will be responsive to therapy in the populations and contexts being studied.
NIH-PA Author Manuscript
Keywords aging; dementia; stress; endocrine system In recent years there has been increased emphasis on including biological measures in health care research and in evaluating patient outcomes. The National Institute for Nursing Research (NINR) has emphasized the need for more biobehavioral research (https:// www.ninr.nih.gov/sites/www.ninr.nih.gov/files/ninr-strategic-plan-2011.pdf) and the Institute of Medicine (IOM) of the National Academies (IOM, 2010) released a report discussing the issues associated with using biological measures as surrogate endpoints for patient outcomes. Biobehavioral research is grounded in the premise that understanding and influencing health outcomes is enhanced through examining the links between biological, psychosocial, and behavioral factors and health status/outcomes (Pellmar, Brandt, & Baird, 2002). This is a worthy goal; however, the success of biobehavioral science in making new Correspondence concerning this article should be addressed to: Christine R. Kovach, College of Nursing, University of Wisconsin Milwaukee, 1921 E Hartford Ave, Milwaukee, WI 53201-0413. [email protected]. The authors declare no conflict of interest.
Kovach et al.
Page 2
NIH-PA Author Manuscript
inroads that influence health outcomes is dependent on understanding and attending to the complexities of a host of specialized conceptual and methodological challenges associated with using biological measures in research.
NIH-PA Author Manuscript
As noted in the IOM report cited above, consistent scientific processes and frameworks are needed in order to ensure the rigorous and transparent use of biological measures. In addition to possibly being invasive and costly, given the state of the science, the selection and interpretation of biological measures must be done with caution. For some biological measures we are lacking strong evidence on the natural history of variability over time and on predictors of variability in the measure. There is a need to build a strong research base on the ability of biological measures to capture meaningful change and to determine minimum clinically important differences (MCID). The purpose of this article is to explore some issues regarding the use of biological measures as outcomes in nursing studies. Data from a study testing the effects of a nurse assessment and treatment protocol used to treat nursing home (NH) residents with dementia are presented (Kovach, Logan, et al., 2006). The purpose of these results is not to look for treatment effects; rather it is to highlight the specific methodological issue of measurement responsiveness to therapy. Effect sizes (ES) for salivary cortisol, observer-rated pain and agitation are presented for two groups of NH residents who were being assessed and treated for new problems over six weeks. For this secondary analysis we compared NH residents who developed new acute psychotic symptoms to NH residents who developed other new problems (e.g. arthrtitic pain, constipation, infection). Because acute psychosis is associated with high stress, these two groups provided an opportunity to examine outcomes following treatment in two different populations.
MCID AND RESPONSIVENESS TO CHANGE The determination of MCID is needed for evaluating the clinical meaningfulness of statistically significant research findings. MCID is defined as an estimation of the smallest difference in a measurable clinical parameter that indicates a meaningful change in a health care outcome (Kiley, Sri Ram, Croxton, & Weinmann, 2005). The development and use of standardized MCIDs will increase the evidence-base for nursing practice, assist in making decisions regarding resource allocation, and allow clearer interpretation of research findings.
NIH-PA Author Manuscript
While MCIDs have value, there are notable challenges to developing metrics for MCIDs (Gilbert, Brown, Cappelleri, Carlsson, & McKenna, 2009; Jordon, Dunn, Lewis & Croft, 2006). Even with fairly well-accepted biological measures, it is possible that as science develops we will learn that a measure may be able to detect change under some conditions, but not under other conditions. Therefore it is important to consider theory, previous research, and the expected change from treatment when deciding if it is reasonable to select a particular biological measure for a specific study. An essential quality of the measure used to develop the MCID, is the ability to accurately detect health change in response to a specific treatment or stimuli. The measure should validly represent the intended construct. While determining this is not trivial, it can be particularly challenging for biological measures which may have well-established measurement validity for the biological phenomenon being measured (e.g., it validly measures the serum level of a hormone) but which may, or may not have, well-established measurement validity for the intended outcome construct of the study (e.g., stress). In addition, the outcome measure used should remain relatively unchanged if the treatment is not administered (i.e., it must have test-retest reliability), there must be room for change on the measure (e.g., it should not have a floor or ceiling effect), and the timing of measurement must be appropriate for the onset and duration of the intervention’s effect.
Res Gerontol Nurs. Author manuscript; available in PMC 2015 March 01.
Kovach et al.
Page 3
NIH-PA Author Manuscript
Once a measure is deemed reasonable, pilot work can estimate the direction and magnitude of changes on the measure following the proposed treatment or stimuli condition. This estimate can be used in ad hoc power analysis and to determine if the estimated amount of change is clinically significant. A statistically significant change in group scores following treatment on a biomarker does not necessarily indicate an important change in health or quality of life. In order for a biomarker to qualify as a MCID, the change in score needs to relate to other measures (Jordon et al., 2006). For example, in people with dementia, these might include family report of improvement or changes in psychotropic drug use. The change in the biomarker should also not have a negative consequence on the overall health status of the individual. For example ezetimibe significantly lowers cholesterol but is related to severe hepatic side effects (Stolk, Becx, Kuypers & Seldenrijk, 2006).
BACKGROUND TO STUDY OF PEOPLE WITH ADVANCED DEMENTIA
NIH-PA Author Manuscript
The Serial Trial Intervention (STI) is a decision support tool to address the problem of under assessment and treatment of newly emerging problems of nursing home residents with advanced dementia that are unable to clearly or consistently verbally report symptoms. The estimates of treatment effect used in this study are based on data from a parent study that compared the effects of two versions of a nursing assessment and treatment protocol (5-step and 9-step Serial Trial Intervention) on stress, pain, and agitation among NH residents with advanced dementia (Kovach et al., 2012). The 5-step version of the STI was tested for the outcomes of pain and agitation and found to be effective when compared to standard care (Kovach, Kelber, Simpson, & Wells, 2006). However, it was also found that thoughtful follow through was often lacking as evidenced by failure to get effective treatments scheduled for regular use and failure to add adjunctive and preventive therapies to the therapeutic regimen (Kovach, Cashin, et al., 2006). The 9step version attempted to address these deficits by adding steps that directed nurses to provide more long-term and more comprehensive treatments and to perform more thorough evaluations (Kovach et al., 2012).
NIH-PA Author Manuscript
The physical condition and functional limitations of people with advanced dementia pose challenges to measurement of variables of interest in nursing research. People with advanced dementia have communication and cognitive deficits that preclude the use of most selfreport measures. Proxy reports from family and professional caregivers on measures such as pain are highly biased. For example, multiple studies have found that family and professional caregivers grossly underestimate pain and depression in people with dementia (Horgas & Dunn, 2001; Cohen-Mansfield & Lipson, 2002). Also, invasive measures or those that involve application of sensors to the body may induce a response that confounds the measurement (Aung et al., 2008). The use of physiological variables to measure indices of stress and depression has been driven, in part, by technological advances that enable the noninvasive measurement of some biological measures. Cortisol can be easily accessed by saliva collection that can be accomplished in everyday contexts with minimal interruption to the natural flow of activities. This is an important consideration for debilitated NH residents. Several studies have demonstrated a strong correlation (r = .805) between time-matched salivary and plasma cortisol (Hellhammer, Wust, & Kudielka, 2009; Kirschbaum & Hellhammer, 1994; Pruessner et al., 1997). Saliva collection has been shown to be well tolerated by NH residents (Woods et al., 2008). The acceptability of saliva collection is important so that cortisol levels are not confounded by an induced stress response from sample collection.
Res Gerontol Nurs. Author manuscript; available in PMC 2015 March 01.
Kovach et al.
Page 4
These samples are also stable for up to 2 weeks at room temperature (Malamud, 1992), thus eliminating the need for immediate freezing.
NIH-PA Author Manuscript
Key conceptual issues in attempting to incorporate cortisol as an outcome measure into intervention studies for intervention studies include justifications for : a) cortisol as a marker of physical and emotional stress; b) the ability of people with dementia to experience stress from a threat or challenge; and c) the relationship of treatment of the threat or challenge to lower stress. While salivary cortisol has been used as a measure in psychophysiological research for the past 20 years (Kirschbaum & Hellhammer, 1989), this measure has begun to be used more recently in nursing and dementia care research (Hanrahan, McCarthy, Kleiber, Lutgendorf, & Tsalikian, 2006; Herrington, Olomu, & Geller, 2004; Williams, Hagerty, & Brooks, 2004; Woods & Dimond, 2002; Woods & Martin, 2007). Salivary cortisol is frequently used as a biomarker of psychological stress (Piazza, Almeida, Dmitrieva, & Klein, 2010) and measurement of cortisol in saliva provides a reliable marker of stress resulting from both physical discomfort and emotional stress (Chrousos, 2011; Weibel, 2003; Young, Abelson, & Lightman, 2004).
NIH-PA Author Manuscript
Stress is defined as a physiological response of the body to situations or stimulus that are perceived as dangerous or threatening. People with dementia have a decreased threshold for tolerating such stressors (Lawton, 1986; Hall & Buckwalter, 1987). Multiple studies have shown an association between stress, emotional arousal and salivary cortisol levels (Blair et al, 2008; El-Sheikh, Erath, Buckhalt Granger, & Mize, 2008; Fortunato, Dribin, Granger, & Buss, 2008). Age can influence cortsiol values. The most consistent finding with advanced age is an increase in the nighttime nadir which flattens the slope (Ice, 2005; Fiocco, Wan, Weekes, Pim, & Lupien, 2006; Raff et al, 1999; Smyth et al, 1997). Treatment of physical and emotional stress is associated with lowering of cortisol level (Carlson, Speca, Patel & Goodey, 2004; Gaab, Blattler, Menzi, Pabst, Stoyer & Ehlert, 2003; Woods & Dimond, 2002).
METHODS Design and Sample
NIH-PA Author Manuscript
Study participants for this secondary analysis were from twelve NHs, all of which had a typical schedule of early awakening (i.e. 5:00 a.m. to 8:00 a.m.) and early bedtime (5:40 p.m. to 8:00 p.m.). The inclusion criteria from the parent study were that the person had a diagnosis of a dementing illness, had no other chronic psychiatric diagnosis, had no known diseases of the hypothalamic-pituitary-adrenal axis, was not taking a corticosteroid, had a pre-study length of stay in the NH of at least 4 weeks, and had no diagnosed acute illness at pretesting. Participants from the two study conditions were combined because the direction and magnitude of effects for the two-week time period examined in the data used for this study were similar across the two versions of the protocol. The study was approved by the Institutional Review Board. Written consent was obtained from the NH resident’s guardian and verbal assent was obtained from each participant asked to participate. While all participants provided assent, five participants clearly refused or expressed displeasure regarding saliva collection. Samples were not collected when a participant refused or expressed any sign of displeasure regarding the data collection. It is worth noting that as is typical for NH residents, many patients were being treated for common conditions that included infection (e.g., of the skin, urinary tract, respiratory tract, or gastrointestinal tract), pain (e.g., musculoskeletal or neuropathic), mobility or body alignment problems, skin breakdown, constipation, leg swelling from venous insufficiency, impacted cerumen, poor dentition, and dysphagia. For the current study two samples were
Res Gerontol Nurs. Author manuscript; available in PMC 2015 March 01.
Kovach et al.
Page 5
identified: participants being treated for new acute problems without acute psychosis (n = 95) and participants who were being treated for new acute psychotic symptoms (n = 16).
NIH-PA Author Manuscript
Thirty-one NH residents from the parent study were excluded from this study: 10 were in the dying process, 9 were hospitalized for acute illness (e.g. stroke, bradycardia, heart failure, unresponsive episode), 6 had saliva containing exogenous hydrocortisone documented by liquid chromatograph/tandem mass spectrometry (Raff & Singh, 2012), and 6 had missing saliva samples due to collection refusal (n =5) or quantity not sufficient (n =1). Measures and Procedures
NIH-PA Author Manuscript
Salivary cortisol was used to measure HPA axis response to stress (Raff, 2000). The Wisconsin Agitation Intensity (WAI) Scale, used to measure agitated behavior, is an observational scale that uses number, duration and intensity of behaviors as parameters for agitation severity. Possible scores are 0 to 100. Interrater reliability using this tool is .95–.98 and the scale demonstrated responsiveness to change following intervention (Kovach et al., 2004). Pain was assessed using the 9-item Discomfort-DAT scale (Hurley, Volicer, Hanrahan, Houde, & Volicer, 1992). Possible scores are 0 to 75. It is an observational tool that assesses overall level of discomfort rather than pain in response to acute stimuli. Internal consistency alpha coefficients have been reported between .86 and .89 (Hurley et al., 1992) and interrater reliability of .9 (Kovach, Noonan et al., 2006). In the latter study, which was a randomized experiment, the tool demonstrated responsiveness to change following intervention. Saliva and observation-based measures of agitation and pain were collected on the same weekday, both before the nurses began using the assessment and treatment protocol and two weeks after treatment was initiated. Three nurse research assistants, not employed by the nursing homes, were trained by the principal investigator to screen for eligibility, to conduct unobtrusive observations of agitation and pain, and to collect the saliva samples. Data collectors were blinded to study conditions.
NIH-PA Author Manuscript
Measures of pain and agitation were collected at least 30 minutes past the time of any potentially discomfort or stress-producing event (e.g., bath, medical exam). Since agitation typically fluctuates over the day, multiple measurements at various time points are recommended to provide a reasonable measure of overall agitation (Kovach et al., 2004). Eight agitation measures were taken per day (2 during breakfast, midmorning, before and after dinner). To capture possible differences in overall level of discomfort in the morning and afternoon, two Discomfort-DAT measures were taken per day. To derive an overall assessment of daily pain and agitation, scores were averaged to yield one pretest and one posttest score on each measure for each study participant. Evidence supports the use of a similar physiological stimulus such as food intake during regular mealtimes to stimulate the HPA axis and control for some intraindividual variation in diurnal rhythm (Gibson et al., 1999; Rosmand, Holm, & Bjorntorp, 2000). It is also recommended that saliva for cortisol assay be obtained close to awakening and bedtime to capture diurnal variation in cortisol levels (Stone et al., 2001). Because residents of many nursing homes retire to bed early in the evening, 45 minutes after dinner was a feasible data collection time that is close to nadir. Four saliva samples were collected (±15 minutes) from under the tongue: 30 minutes after waking (T1-waking), 45 minutes after breakfast (T2-morning), and 45 minutes before (T3afternoon) and after dinner (T4-evening). Following collection, samples were inserted into a cryogenic vial or storage tube, centrifuged, batched by subject, and frozen at −20°C. Saliva samples were analyzed using an FDA-cleared cortisol ELISA (Salimetrics, LLC, State College, PA; Raff, Homar, & Skoner, 2003). Samples from each subject were assayed in one batch. The intraassay imprecision, expressed as a coefficient of variation, (CV) was Res Gerontol Nurs. Author manuscript; available in PMC 2015 March 01.
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5.2% at 3.1 (SD, 0.2) nmol/L (n = 10) and 2.6% at 10.4 (0.3) nmol/L (n = 10). Intrassay imprecision is the analytical error for samples analyzed within a single run of the assay. In the current study, samples from each subject were analyzed within one run to minimize interassay imprecision described below. It is typical of immunoassays to have higher CVs at the lowest concentrations of the analyte measured. It is important to note that an intraassay CV of
